POS0500 LEVELS OF IL-6 AND OTHER INFLAMMATORY PROTEINS IN EARLY RA PREDICT JOINT DAMAGE PROGRESSION OVER 5 YEARS
Authors: E. Rydell, K. Forslind, L. T. H. Jacobsson, C. Turesson
Journal: Annals of the Rheumatic Diseases (2022)

Background Joint damage in rheumatoid arthritis (RA) remains a significant problem. Identification of biomarkers associated with joint destruction can improve our understanding of underlying disease processes and future management. Objectives To evaluate inflammatory proteins as potential predictors of radiographic progression of joint damage. Methods Consecutive early RA patients (symptom duration &lt;12 months), recruited 1995-2005 from a defined area, were followed through 5 years in an observational study. Radiographs of hands and feet were scored in chronological order by a trained reader according to the modified Sharp-van der Heijde score (SHS). Stored plasma samples from the baseline visit were analyzed for levels of 92 inflammatory proteins (Inflammation panel by O-link). Statistical analyses were pre-designated as hypotheses-driven or exploratory. For the latter, principal component analysis was used to identify groups of proteins that explain the variance in the proteome. Within components selected based on Eigenvalues, proteins with a factor loading of &gt;0.50 were investigated as potential predictors of radiographic progression. Logistic and linear regression models were used to assess associations with rapid radiographic progression (RRP; ≥5 SHS/year) and progression of SHS over 5 years. Results Data on baseline levels of proteins, and radiographs at baseline and 5 years were available for 114 patients. The median progression of SHS was 11 (interquartile 2-19). For potential biomarkers with an a priori hypothesis, IL-6 significantly predicted both RRP and progression of SHS over 5 years analyzed as a continuous variable [adjusted ß = 0.09 per SD, p=0.032, adjusted for rheumatoid factor (RF) and baseline SHS]. A significant positive association for matrix metalloproteinase 1 (MMP-1) was observed in the unadjusted analysis for SHS progression, but not for RRP (Table 1). In the exploratory analyses, S100 calcium-binding protein A12 (EN-RAGE) was positively, and TNF-related apoptosis-inducing ligand (TRAIL) negatively associated with both outcomes. Table 1. Baseline inflammatory protein biomarkers and progression of joint damage over 5 years in rheumatoid arthritis Rapid radiographic progression SHS progression (continuous) Crude Adjusted* Crude Adjusted* Variables OR 95% CI P P (corr)§ OR 95% CI P P (corr)§ Beta 95% CI P P (corr)§ Beta 95% CI P P (corr)§ A priori hypothesis° IL-6 1.83 1.11-3.01 0.018 0.14 1.62 0.96-2.75 0.072 0.58 0.14 0.06-0.23 0.002 0.016 0.09 0.01-0.17 0.032 0.26 MMP-1 1.56 0.92-2.66 0.10 0.55 1.44 0.84-2.47 0.19 0.96 0.11 0.02-0.20 0.019 0.13 0.08 -0.01-0.16 0.072 0.50 Exploratory analyses † MCP-3 1.64 1.01-2.65 0.045 1.99 1.14-3.49 0.016 0.03 -0.07-0.12 0.57 0.04 -0.05-0.12 0.39 CDCP1 1.76 1.07-2.91 0.027 2.14 1.22-3.78 0.009 0.06 -0.03-0.15 0.19 0.08 -0.00-0.16 0.063 SLAMF1 1.64 1.05-2.57 0.031 1.61 1.01-2.56 0.047 0.06 -0.02-0.15 0.16 0.05 -0.02-0.13 0.15 TNFSF14 1.67 1.08-2.60 0.022 1.53 0.98-2.37 0.060 0.07 -0.02-0.15 0.12 0.04 -0.04-0.11 0.30 EN-RAGE 2.77 1.56-4.94 0.001 2.44 1.34-4.43 0.004 0.16 0.08-0.25 &lt;0.001 0.10 0.02-0.19 0.014 LIF 1.96 1.13-3.40 0.017 1.73 0.95-3.14 0.073 0.11 0.02-0.20 0.019 0.06 -0.03-0.15 0.18 Flt-3L 0.60 0.36-0.98 0.040 0.68 0.40-1.14 0.15 -0.11 -0.20-’-0.03 0.011 -0.07 -0.15-0.01 0.075 DNER 0.72 0.42-1.25 0.25 0.69 0.37-1.27 0.23 -0.10 -0.19-’-0.00 0.049 -0.08 -0.17-0.00 0.054 CD8A 0.74 0.49-1.12 0.16 0.85 0.55-1.31 0.45 -0.09 -0.17-’-0.01 0.031 -0.05 -0.12-0.03 0.23 TRAIL 0.50 0.30-0.83 0.007 0.51 0.29-0.88 0.016 -0.12 -0.20-’-0.03 0.007 -0.08 -0.16-0.00 0.048 Variables per SD. * Adjusted for RF and baseline SHS. § Holms correction for multiple testing for a priori hypotheses only. ° No significant associations for TNF-alpha, Osteoprotegerin, IL-17A, CCL11, CCL19 or VEGFA. † Only biomarkers with significant associations shown. Conclusion Plasma levels of IL-6 at RA diagnosis predict degree of future joint damage. EN-RAGE and TRAIL, both modulators of NF-κB which is known to regulate immune response, are potential biomarkers that need further investigation. Disclosure of Interests Emil Rydell: None declared, Kristina Forslind: None declared, Lennart T.H. Jacobsson Consultant of: Novartis, Eli-Lily and Janssen, Carl Turesson Speakers bureau: AbbVie, BMS, Nordic Drugs, Pfizer, Roche, Consultant of: Roche, Grant/research support from: BMS.